Conformational studies on a diastereoisomeric pair of tricyclic nonclassical cannabinoids by NMR spectroscopy and computer molecular modeling.
Among the nonclassical cannabinoids, CP-55,244 (4), which incorporates an axial 14 beta-hydroxymethyl group, is pharmacologically 30 times more potent than its prototype CP-47,497 (2) and 300 times more potent than delta 9-THC (1). It has a high degree of stereoselectivity (about 120:1) with respect to its diastereoisomer, CP-97,587 (5), which differs structurally by having the 14-hydroxymethyl group equatorial. Conformational studies of 4 and 5 were carried out using 2D NMR spectroscopy and molecular modeling in order to define and compare the similarities and differences between them. Specific structural features of interest are the conformation of the 1',1'-dimethylheptyl (DMH) side chain, the conformation of the cyclohexyl rings, the orientation of the phenolic ring (A ring) relative to the cyclohexyl ring (C ring), and the orientation of the hydroxymethyl group as well as the formation of intramolecular hydrogen bonding. Our results show that the conformations of the phenolic hydroxyl (Ph-OH) and DMH side chain for 4 are similar to those of 2. The proton of the phenolic hydroxyl is pointing away from the C ring while the DMH chain randomly adopts one of four dynamically averaged conformers in which it is almost perpendicular to the plane of the aromatic ring. The relative orientation of the A and C rings is such that the two rings interconvert between two low-energy conformations. Compound 5 prefers the conformer with the Ph-OH pointing toward the alpha-face of the cyclohexyl ring, while for 4, there is an increased preference for the conformer where the Ph-OH is directed toward the beta face. This may be due to intramolecular H-bonding between the Ph-OH and the axial 14 beta-hydroxymethyl group of 4 that stabilizes this conformation. Hydrogen bonding between the Ph-OH and the equatorial-14 alpha-hydroxymethyl of 5 was not detected. Thus, the orientation of the aliphatic hydroxyl group with respect to the D ring in 4 and 5 may play an important role with regard to the pharmacophoric requirements of the two analogs for the cannabinoid receptor and provide an explanation for the observed differences in their biological properties.
Xie
X Q
XQ
Institute of Materials Science, School of Pharmacy, University of Connecticut, Storrs 06269, USA.
Pavlopoulos
S
S
DiMeglio
C M
CM
Makriyannis
A
A
D002186:Cannabinoids / Q000737:chemistry*; D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
D002186:Cannabinoids; D009281:Naphthalenes; C065365:CP 55244